Terminology
The terminology is still under discussion. Serrated lesions can be regarded as a continuous spectrum of colorectal lesions with increasingly more pronounced serrated morphology starting with a
hyperplastic polyp (HP) and progressing to
sessile serrated lesions (SSLs, sometimes referred to as
sessile serrated adenomas or
sessile serrated polyps),
traditional serrated adenomas (TSA) and leading, finally, to
adenocarcinoma. Not only the adenomatous component but also other alterations associated with more pronounced serrated morphology may potentially progress to cancer (see Table
2).
Table 2
Continuous spectrum of serrated lesions and possible combinations of histopathologic types
Hyperplastic polyp | No | Minimal |
Sessile serrated lesion | No | Slightly increased but exact data are missing (rapid transformation may be possible in a short time) |
Traditional serrated adenoma | Yes | Increased and suggested worse prognosis than carcinomas arising in sessile serrated lesions |
Mixed polyp | Yes | Increased, but exact data are not available |
Adenoma (tubular, villous) | Yes | Increased, 17 years on average |
The situation involving
sessile serrated lesions is complicated as these lesions only reveal complex structural abnormalities, not adenomatous changes. Therefore, these lesions are neither adenomatous nor are they neoplastic. This is why Kudo et al. [
9] and Lambert et al. [
10] recommended that these lesions no longer be called adenomas; instead they should be referred to as SSLs. Few of these lesions are reported to rapidly progress to invasive carcinoma, [
11]. Those few cases that do progress rapidly, particularly in the right colon, may be expected to appear more frequently as interval cancers. TSAs, unlike SSLs, do contain adenomatous alterations, albeit sometimes quite subtle [
12]; they are therefore termed correctly and treatment and surveillance should correspond to that of adenomas (see Chapters 8 and 9 in the full guideline document [
13,
14]).
Due to the continuous spectrum in the serrated pathway to colorectal cancer, lesions with combinations of serrated morphology and adenomatous cytology can be observed. If more than one histopathologic type in the serrated spectrum (HP, SSL, TSA) is discernible in a given lesion, or at least one type in combination with adenomatous tissue, such lesions are referred to as mixed polyps.
The different histopathologic types (e.g. HP and SSL, SSL and TSA, adenoma and SSL, etc.) must be stated in the diagnosis.
Hyperplastic polyp
Hyperplastic polyps (HPs) are composed of elongated crypts (no complex architecture) with serrated architecture in the upper half of the crypt. These polyps usually show some proliferation in the basal (non-serrated) part of the crypts (regular proliferation). Nuclei are small, regular, basal-orientated and lacking hyperchromasia, but with stratification of the upper (serrated) half of the crypts, and without cytological or structural signs of neoplasia.
Differences in the appearance of the cytoplasma permit recognition of three types:
-
Microvesicular type
-
Goblet-cell-rich type
-
Mucin-poor type.
The microvesicular variant greatly predominates, but distinction between types is subject to wide interobserver variation, especially in small lesions, and is not always possible. Currently, routine subclassification is therefore neither feasible, nor has it been shown to be beneficial.
At the molecular level the microvesicular variant of HP may be the precursor lesion for sessile serrated lesion, and a goblet-cell-rich HP may be the precursor lesion for a traditional serrated adenoma [
15‐
17]. Routine distinction of these types is not necessary.
Sessile serrated lesion
Sessile serrated lesions are described in the literature as “sessile serrated adenoma” and are often found in the right colon. This is a misnomer since sessile serrated lesions do not contain adenomatous changes [
9,
10,
18].
To date, four synonymously used terms exist for these lesions: sessile serrated adenoma [
19], superficial serrated adenoma [
20], type 1 serrated adenoma [
21] and serrated polyp with abnormal proliferation [
17].
We recommend using only the term
sessile serrated lesion and avoiding use of any other terms for this entity. This recommendation is given in full awareness that sessile serrated lesions do not show histological signs of an adenoma, but, like adenomas, they should be excised if detected during an endoscopic examination. Currently, even in the hands of expert GI pathologists, the agreement on the sub-types of serrated lesions is only moderate [
22].
The vast majority of SSLs will not progress to adenocarcinoma. Histological criteria of these sessile, usually larger lesions include an abnormal proliferation zone with structural distortion, usually most pronounced in dilatation of the crypts, particularly near the base. Abundant mucus production is usually also observed as pools of mucin in the lumen of the crypts and on the surface of the mucosa. SSLs are found mainly in the right colon and may be misdiagnosed as hyperplastic polyps. Clues to the correct diagnosis include location and large size. As discussed above, cytological signs of “neoplasia” are lacking, but structural abnormalities are present, i.e. glandular branching [
18].
Sessile serrated lesions have an elevated serration index and serration in the basal half of crypts with basal dilation of crypts. The epithelium/stroma-ratio is believed to be >50% in SSL. There is crypt branching with horizontal growth (above muscularis mucosae; e.g. T- and L-shaped glands) and often pseudoinvasion into the submucosal layer, rectangular dilation of whole crypts with and without presence of mucus, increased number of goblet cells at the base of the crypts, vesicular nuclei with prominent nucleoli and proliferation zone in the middle of the crypts. Currently there is insufficient evidence available in the literature for weighting of these criteria.
A well-oriented polypectomy is mandatory for the identification of such histological features. Correct assessment of the deepest portions of the mucosa is impossible in superficial or tangentially cut lesions [
15,
16].
Further criteria include an often asymmetrical expansion of the proliferation zone into the middle third of crypts. Often mild cytological atypia (slightly enlarged vesicular nuclei, nucleoli) is found without clear signs of neoplasia (dysplasia).
BRAF mutations depend on the type and location of lesion (see Table
3).
Table 3
Prevalence of serrated lesions with BRAF Mutation—a prospective study of patients undergoing colonoscopy
Hyperplastic polyp | 120 (29) | 35 (29) | 85 (71) |
Sessile serrated lesion | 36 (9) | 27 (75) | 9 (25) |
Trad. serrated adenoma | 3 (1) | 2 (66) | 1 (33) |
Mixed polyp | 7 (2) | 4 (57) | 3 (43) |
Tubular adenoma | 237 (57) | 176 (74) | 61 (26) |
Villous adenoma | 11 (3) | 6 (55) | 5 (45) |
Other abnormalities include:
The frequency of sessile serrated lesions in small retrospective series is estimated at 2–11% of all mucosal lesions in the colon [
35,
36]; between 8% and 23% are misdiagnosed as hyperplastic polyps with an interobserver variation of up to 40% [
17,
37‐
39].
The histological features separating HPs from SSLs constitute a continuous spectrum, and intermingled features can often be seen. This could explain the moderate interobserver concordance (
k = 0.47) and the overlapping proliferative activity, and may justify establishing semi-quantitative criteria for diagnosis (e.g. >30% of undifferentiated cells) [
40,
41]. Only a few immunohistochemical markers (Ki67, Ki67 + CK20, MUC6) have been tested for differentiating HPs and SSAs, and their usefulness in colorectal screening and diagnosis remains to be validated [
42,
43]. At present, such an additional immunohistochemical analysis cannot be recommended (see Table
4).
Table 4
Comparison of proliferative activity in adenoma, hyperplastic polyps, sessile serrated lesion and traditional serrated adenoma
Upper 1/3 | 68.8 | 0.1 | 1.6 | 27.9 |
Middle 1/3 | 48.7 | 9.1 | 20.3 | 30.6 |
Lower 1/3 | 29.6 | 60.3 | 64.9 | 38.2 |
In all likelihood, lesions formerly interpreted as
mixed hyperplastic and
adenomatous polyp are, in fact, SSLs complicated by conventional neoplasia, [
44]. Special care must be taken in such cases to document the respective histopathologic components in such mixed polyps. Sometimes the conventional neoplastic part shows features other than in classical adenomas. The nuclei are prominent, less palisading and smaller than in classical adenomas. It is not clear whether this type of morphology is distinct for serrated lesions and whether any clinical implications can be drawn.
Prospective studies with risk stratification are needed to develop more precise methods of diagnosis and recommendations for classification. Sessile serrated lesions appear to take a long time (average 17 years) to develop into an invasive carcinoma. In contrast, an ill-defined, small subsample of SSLs seems to rapidly progress [
11,
44]. Therefore, SSLs should be completely excised, particularly if they are located on the right side of the colon [
16,
45].
Diagnosis on a biopsy is not adequate to exclude SSL since the most severe histologic changes might only appear focally within a lesion that otherwise appears to be a hyperplastic polyp [
46].
The German guidelines for colorectal cancer [
47] recommend complete removal and follow-up of SSL similar to adenomas. An intensive surveillance protocol is recommended for sessile serrated lesions (surveillance colonoscopy after 3–5 years subsequent to complete excision of non-neoplastic SSL, after 1 year after excision of SSL HGIEN [
47]).
The UK Guidelines [
48‐
51] recommend complete excision but classify these lesions in the same risk category as hyperplastic polyps. The existing evidence base is not definitive as to the level of risk, and follow-up decisions should be made locally until more evidence is forthcoming.
Mixed polyp
A mixed polyp may contain partially hyperplastic, classical adenomatous or traditional serrated adenoma or sessile serrated lesion components. Rather than a continuous spectrum such lesions most probably represent several evolutionary lines, depending on the order of certain abnormalities in genes such as
APC,
BRAF and
KRAS [
15,
16]. It has to be determined whether mixed polyps represent serrated lesions complicated by conventional neoplasia [
53].
Focal, hyperplastic-like narrowing of the basal region of a few crypts in SSL and the findings of flat sectors or
ectopic crypt formation in SSL/TSA [
43] are examples of combinations of serrated and adenomatous components. However, these features add no information of further diagnostic value; they probably result from the continuous developing nature of serrated lesions. We therefore recommend that the diagnosis of mixed polyp should be restricted to the definition given above under
Terminology (i.e. lesions with—
…more than one histopathologic type in the serrated spectrum (HP, SSL, TSA
) … or at least one type in combination with adenomatous tissue…). Mixed polyps are serrated lesions in which more than one histopathologic type in the serrated spectrum (HP, SSL, TSA) is discernible in a given lesion or at least one type in combination with classical (unserrated) adenomatous tissue. The different histopathological types must be mentioned in the diagnosis, e.g. mixed polyp (HP and SSL, adenoma and SSL).
Risk of progression
The vast majority of hyperplastic polyps and serrated lesions will not undergo malignant transformation. Only a fraction, especially in the group of sessile serrated lesions, may progress to rapidly aggressive carcinoma [
35,
54].
Hyperplastic polyps rarely progress to carcinoma. A single case report can be found in the literature [
55] and a second (unpublished) case has been reported in southern Germany. Interestingly, these carcinomas show features of gastric differentiation.
Little evidence is available on which the risk of colorectal cancer associated with serrated lesions other than hyperplastic polyps could be reliably judged. The risk assessment for sessile serrated lesions is not yet defined, but a subset of these lesions appears to give rise to carcinoma often less than a few millimeters in size. In a series of 110 traditional serrated adenomas, 37% exhibited foci of significant neoplasia and 11% contained areas of intramucosal carcinoma [
12]. Mixed polyps (e.g., HP/TSA/SSL or HP/adenoma) seem to have at least the same rate of progression to colorectal carcinoma as adenomas, and the risk might be higher [
56,
57].